Study of Vintafolide (MK-8109, EC145) for the Treatment of Recurrent or Refractory Solid Tumors (MK-8109-006, EC-FV-01)

Protocol EC-FV-01: A Phase 1 Study of EC145 Administered in Weeks 1 and 3 of a 4-Week Cycle

This is a Phase I clinical trial evaluating the safety and tolerability of escalating doses of vintafolide (EC145) in participants with relapsed or refractory advanced tumors. The primary objective of this study is to determine the safety and maximum tolerated dose of vintafolide given by intravenous bolus or infusion. The efficacy of the treatment will also be measured.

Study Overview

• Status: Completed
• Conditions: Cancer
• Intervention / Treatment: Drug: Vintafolide IV Bolus; Drug: Vintafolide IV Infusion

Detailed Description

This is a dose escalation study of vintafolide administered by intravenous (IV) bolus or infusion during weeks 1 and 3 of a 4-week cycle to participants with solid tumors refractory to current therapies. Vintafolide is a drug that is specifically designed to enter cells via a folate vitamin receptor. Experimental evidence shows that the target receptor is over-expressed in many human cancers. There are no previous human studies of vintafolide treatment; however, lab research (research in test tubes and/or animals) using vintafolide has shown activity against tumors in animals. This activity in animal models suggests that vintafolide may be useful as chemotherapy against human cancers.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological or cytological diagnosis of neoplasm
• No effective standard therapeutic options
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• >=4 weeks post therapeutic radiation of chemotherapy >=6 weeks for nitrosoureas and mitomycin C) and recovery from associated toxicities
• Negative serum pregnancy test for women of child-bearing potential and willingness to practice contraceptive methods
• Adequate bone marrow reserve, renal, and hepatic function

Exclusion Criteria:

• Concurrent hematological malignancies
• Women who are pregnant or lactating
• Evidence of symptomatic brain metastases
• Receiving concomitant anticancer therapy (excluding supportive care)
• Requires palliative radiotherapy at time of study entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vintafolide 1.2 mg IV Bolus; Vintafolide 1.2 mg administered by IV bolus on Days 1, 3, 5, 15, 17, and 19 of 4-week treatment cycles	Drug: Vintafolide IV Bolus; Vintafolide is a folic acid desacetylvinblastine hydrazide conjugate
Experimental: Vintafolide 2.5 mg IV Bolus; Vintafolide 2.5 mg administered by IV bolus on Days 1, 3, 5, 15, 17, and 19 of 4-week treatment cycles	Drug: Vintafolide IV Bolus; Vintafolide is a folic acid desacetylvinblastine hydrazide conjugate
Experimental: Vintafolide 4.0 mg IV Bolus; Vintafolide 4.0 mg administered by IV bolus on Days 1, 3, 5, 15, 17, and 19 of 4-week treatment cycles	Drug: Vintafolide IV Bolus; Vintafolide is a folic acid desacetylvinblastine hydrazide conjugate
Experimental: Vintafolide 2.5 mg IV Infusion; Vintafolide 2.5 mg administered by a 1-hour IV infusion on Days 1, 3, 5, 15, 17, and 19 of 4-week treatment cycles	Drug: Vintafolide IV Infusion; Vintafolide is a folic acid desacetylvinblastine hydrazide conjugate
Experimental: Vintafolide 3.0 mg IV Infusion; Vintafolide 3.0 mg administered by a 1-hour IV infusion on Days 1, 3, 5, 15, 17, and 19 of 4-week treatment cycles	Drug: Vintafolide IV Infusion; Vintafolide is a folic acid desacetylvinblastine hydrazide conjugate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose During Cycle 1 Treatment	Maximum Tolerated Dose (MTD) was defined as the highest dose that can safely be administered to a patient to produce acceptable, manageable and reversible toxicity. This level was further defined as the dose level at which no more than 1 of 6 participants had dose-limiting toxicity (DLT) and the level below the dose at which ≥2 of 6 participants had DLT.	Up to Day 26 in Treatment Cycle 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Best Overall Tumor Response: Participants with Folate Receptor Positive Tumors at Baseline	Tumor status was assessed according to Response Evaluation Criteria in Solid Tumors. Tumor responses used as a reference the sum of the longest diameter (LD) of the target lesions using imaging studies. Partial Response was defined as ≥30% decrease in LD. Stable Disease was defined as neither sufficient shrinkage or increase in LD to qualify as either Partial Response or Progressive Disease. Progressive Disease was defined as ≥20% increase in LD.	Up to Week 24
Number of Participants with a Dose-Limiting Toxiciity During Cycle 1 Treatment	Dose limiting toxicity was defined as an adverse event that is likely related to the study medication, and fulfills any one of the following criteria: Grade 2 non-hematological toxicity that fails to recover to a Grade 1 level or Baseline at the time that the next treatment cycle is due (with the exception of alopecia); Grade 3 non-hematological toxicity (except for nausea/vomiting without maximal symptomatic / prophylactic treatment); Grade 4 hematological toxicity; Toxicity that, in the opinion of the investigator, would prevent use of the drug dose or regimen by the general oncology community.	Up to Day 26 in Treatment Cycle 1
Number of Participants with an Adverse Event Leading to Study Discontinuation During Cycle 1 Treatment	An adverse event was defined as any untoward, undesired, or unplanned clinical event in the form of physical signs, symptoms, disease, laboratory or physiological observations in a participant administered the Sponsor's product whether or not related to the use of the product	Up to Day 26 in Treatment Cycle 1
Number of Participants with Best Overall Tumor Response: All Treated Participants	Tumor status was assessed according to Response Evaluation Criteria in Solid Tumors. Tumor responses used as a reference the sum of the longest diameter (LD) of the target lesions using imaging studies. Complete Response was defined as disappearance of all target lesions. Partial Response was defined as ≥30% decrease in LD. Stable Disease was defined as neither sufficient shrinkage or increase in LD to qualify as either Partial Response or Progressive Disease. Progressive Disease was defined as ≥20% increase in LD.	Up to Week 24
Maximum Plasma Concentration (Cmax) of Vintafolide on Day 1 of Treatment Cycle 1	Blood was collected from participants for determination of plasma vintafolide. The lower limit of quantitation for vintafolide was 10 ng/mL.	Up to 90 minutes after IV bolus dosing and up to 60 minutes after the start of the 1-hour IV infusion on Day 1 of treatment cycle 1
Maximum Plasma Concentration (Cmax) of Vintafolide on Day 3 of Treatment Cycle 1	Blood was collected from participants for determination of plasma vintafolide. The lower limit of quantitation for vintafolide was 10 ng/mL.	Up to 90 minutes after IV bolus dosing and up to 60 minutes after the start of the 1-hour IV infusion on Day 3 of treatment cycle 1
Area Under the Plasma Concentration-Time Curve (AUC) of Vintafolide on Day 1 of Treatment Cycle 1	Blood was collected from participants for determination of plasma vintafolide. The lower limit of quantitation for vintafolide was 10 ng/mL.	Up to 90 minutes after IV bolus dosing and up to 60 minutes after the start of the 1-hour IV infusion on Day 1 of treatment cycle 1
Area Under the Plasma Concentration-Time Curve (AUC) of Vintafolide on Day 3 of Treatment Cycle 1	Blood was collected from participants for determination of plasma vintafolide. The lower limit of quantitation for vintafolide was 10 ng/mL.	Up to 90 minutes after IV bolus dosing and up to 60 minutes after the start of the 1-hour IV infusion on Day 3 of treatment cycle 1

Collaborators and Investigators

• Sponsor: Endocyte

Publications and helpful links

General Publications

• Li J, Sausville EA, Klein PJ, Morgenstern D, Leamon CP, Messmann RA, LoRusso P. Clinical pharmacokinetics and exposure-toxicity relationship of a folate-Vinca alkaloid conjugate EC145 in cancer patients. J Clin Pharmacol. 2009 Dec;49(12):1467-76. doi: 10.1177/0091270009339740. Epub 2009 Oct 16.
• Lorusso PM, Edelman MJ, Bever SL, Forman KM, Pilat M, Quinn MF, Li J, Heath EI, Malburg LM, Klein PJ, Leamon CP, Messmann RA, Sausville EA. Phase I study of folate conjugate EC145 (Vintafolide) in patients with refractory solid tumors. J Clin Oncol. 2012 Nov 10;30(32):4011-6. doi: 10.1200/JCO.2011.41.4946. Epub 2012 Oct 1.

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): August 1, 2007
• Study Completion (Actual): July 1, 2008

Study Registration Dates

• First Submitted: March 27, 2006
• First Submitted That Met QC Criteria: March 27, 2006
• First Posted (Estimate): March 29, 2006

Study Record Updates

• Last Update Posted (Estimate): December 19, 2014
• Last Update Submitted That Met QC Criteria: December 18, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Cancer; Refractory; Phase I; Solid Tumors; Recurrent; Experimental; EC145
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Folic Acid; Vinca Alkaloids
• Other Study ID Numbers: 8109-006; EC-FV-01 (Other Identifier: Endocyte)